A 3-year-old boy is brought to the child psychiatry clinic by his parents with concerns about developmental delay and social withdrawal. On evaluation, he shows restricted repetitive behaviours, poor eye contact, and delayed speech. Which is the most common associated genetic finding in Autism Spectrum Disorder?

## Genetic Basis of Autism Spectrum Disorder ### Most Common Genetic Finding **Key Point:** Copy number variations (CNVs) and recurrent deletions/duplications in chromosomal regions 16p11.2 and 22q11.2 are the most frequently identified genetic abnormalities in ASD, accounting for approximately 1–3% of cases with identifiable genetic causes. ### Pathophysiology of CNVs in ASD 1. **16p11.2 region** — contains genes involved in synaptic plasticity and neuronal development; deletions and duplications both increase ASD risk 2. **22q11.2 region** — overlaps with DiGeorge syndrome locus; associated with social communication deficits 3. These variants disrupt normal neurodevelopmental pathways, leading to altered synaptic connectivity and impaired social-cognitive processing ### Comparative Frequency of Genetic Associations | Genetic Condition | Prevalence in ASD | Key Feature | |---|---|---| | **CNVs (16p11.2, 22q11.2)** | **1–3%** | **Most common identifiable genetic cause** | | Fragile X syndrome | 0.5–1% | X-linked; intellectual disability prominent | | Tuberous sclerosis | 0.5–1% | Hamartomas; seizures common | | Down syndrome | <0.5% | Trisomy 21; intellectual disability | **High-Yield:** While many genetic variants contribute to ASD (oligogenic inheritance), CNVs in specific hotspot regions (16p11.2, 22q11.2, 7q11.23) are the most reproducibly identified and tested in NEET PG examinations. ### Clinical Pearl **Warning:** Do not confuse "most common genetic finding" with "most common comorbid condition." Intellectual disability co-occurs in ~30% of ASD cases, but this is a phenotypic overlap, not a genetic cause. Fragile X syndrome is an important syndromic cause of ASD but is less frequent than CNVs. ### Diagnostic Approach When evaluating a child with ASD, genetic testing (chromosomal microarray, whole-exome sequencing) is now recommended as first-line investigation to identify CNVs and other pathogenic variants, particularly in children with developmental regression or dysmorphic features.